Cancer is a disease resulting from an abnormal growth of tissue. Certain cancers have the potential to invade into local tissues and also metastasize to distant organs. This disease can develop in a wide variety of different organs, tissues and cell types. Therefore, the term “cancer” refers to a collection of over a thousand different diseases.
Over 4.4 million people worldwide were diagnosed with breast, colon, ovarian, lung, or prostate cancer in 2002 and over 2.5 million people died of these devastating diseases (Globocan 2002 Report). In the United States alone, over 1.25 million new cases and over 500,000 deaths from cancer were predicted in 2005. The majority of these new cases were expected to be cancers of the colon (˜100,000), lung (˜170,000), breast (˜210,000) and prostate (˜230,000). Both the incidence and prevalence of cancer is predicted to increase by approximately 15% over the next ten years, reflecting an average growth rate of 1.4% (American Cancer Society, Cancer Facts and Figures 2005).
Cancer treatments are of two major types, either curative or palliative. The main curative therapies for cancer are surgery and radiation. These options are generally successful only if the cancer is found at an early localized stage (Gibbs J B, 2000). Once the disease has progressed to locally advanced cancer or metastatic cancer, these therapies are less effective and the goal of therapy aims at symptom palliation and maintaining good quality of life. The most prevalent treatment protocols in either treatment mode involve a combination of surgery, radiation therapy and/or chemotherapy.
Cytotoxic drugs (also known as cytoreductive agents) are used in the treatment of cancer, either as a curative treatment or with the aim of prolonging life or palliating symptoms. Cytotoxics may be combined with radiotherapy and/or surgery, as neo-adjuvant treatment (initial chemotherapy aimed at shrinking the tumor, thereby rendering local therapy such as surgery and radiation more effective) or as adjuvant chemotherapy (used in conjunction or after surgery and/or localized therapy). Combinations of different drugs are frequently more effective than single drugs: they may provide an advantage in certain tumors of enhanced response, reduced development of drug resistance and/or increased survival. It is for these reasons that the use of combined cytotoxic regimens in the treatment of many cancers is very common.
Cytotoxic agents in current use employ different mechanisms to block proliferation and induce cell death. They can be generally categorized into the following groups based on their mechanism of action: the microtubule modulators that interfere with the polymerization or depolymerization of microtubules (e.g. docetaxel, paclitaxel, vinblastine, vinorelbine); anti-metabolites including nucleoside analogs and other inhibitors of key cellular metabolic pathways (e.g. capecitabine, gemcitabine, methotrexate); agents that interact directly with DNA (e.g. carboplatin, cyclophosphamide); anthracycline DNA interchalators that interfere with DNA polymerase and Topoisomerase II (e.g. doxorubicin, epirubicin); and the non-anthracycline inhibitors of Topoisomerase II and I enzymatic activity (e.g. topotecan, irinotecan, and etoposide). Even though different cytotoxic drugs act via different mechanisms of action, each generally leads to at least transient shrinkage of tumors.
Cytotoxic agents continue to represent an important component in an oncologist's arsenal of weapons for use in fighting cancer. The majority of drugs currently undergoing late Phase II and Phase III clinical trials are focusing on known mechanisms of action (tubulin binding agents, anti-metabolites, DNA processing), and on incremental improvements in known drug classes (for example the taxanes or the camptothecins). A small number of cytotoxic drugs based on novel mechanisms have recently emerged. Modes of action for these cytotoxics include inhibition of enzymes involved in DNA modification [e.g. histone deacetylase (HDAC)], inhibition of proteins involved in microtubule movement and cell cycle progression (e.g. kinesins, aurora kinase), and novel inducers of the apoptotic pathway (e.g. bcl-2 inhibitors).
The link between activity in tumor cell proliferation assays in vitro and anti-tumor activity in the clinical setting has been well established in the art. For example, the therapeutic utility of taxol (Silvestrini et al. Stem Cells 1993, 11 (6), 528-35), taxotere (Bissery et al. Anti Cancer Drugs 1995, 6 (3), 339), and topoisomerase inhibitors (Edelman et al. Cancer Chemother. 
Cells protect their DNA by adopting a higher-order complex termed chromatin. Chromatin condensation is evident during mitosis and cell death induced by apoptosis while chromatin decondensation is necessary for replication, repair, recombination and transcription. Histones are among some of the DNA-binding proteins that are involved in the regulation of DNA condensation; and post-translational modifications of histone tails serve a critical role in the dynamic condensation/decondensation that occurs during the cell cycle. Phoshorylation of the tails of histone H3 is involved in both transcription and cell division (Prigent et al. J. Cell Science 2003, 116, 3677). A number of protein kinases have been reported to phosphorylate histone H3 and these kinases function both as signal transduction and mitotic kinases.
Even though cytotoxic agents remain in the forefront of approaches to treat patients with advanced solid tumors, their limited efficacy and narrow therapeutic indices result in significant side effects. Moreover, basic research into cancer has led to the investigation of less toxic therapies based on the specific mechanisms central to tumor progression. Such studies could lead to effective therapy with improvement of the quality of life for cancer patients. Thus, a new class of therapeutic agents has emerged, referred to as cytostatics. Cytostatics direct their action on tumor stabilization and are generally associated with a more limited and less aggravating side effect profile. Their development has resulted from the identification of specific genetic changes involved in cancer progression and an understanding of the proteins activated in cancer such as tyrosine kinases and serine/threonine kinases.
In addition to direct inhibition of tumor cell targets, cytostatic drugs are being developed to block the process of tumor angiogenesis. This process supplies the tumor with existing and new blood vessels to support continued nourishment and therefore help promote tumor growth. Key tyrosine kinase receptors including Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), Fibroblast Growth Factor 1 (FGFR1) and Tie2 have been shown to regulate angiogenesis and have emerged as highly attractive drug targets.
To support progressive tumor growth beyond the size of 1-2 mm3, it is recognized that tumor cells require a functional stroma, a support structure consisting of fibroblast, smooth muscle cells, endothelial cells, extracellular matrix proteins, and soluble factors (Folkman, J., Semin Oncol, 2002. 29 (6 Suppl 16), 15-8). Tumors induce the formation of stromal tissues through the secretion of soluble growth factors such as PDGF and transforming growth factor-beta (TGF-beta), which in turn stimulate the secretion of complimentary factors by host cells such as fibroblast growth factor (FGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF). These stimulatory factors induce the formation of new blood vessels, or angiogenesis, which brings oxygen and nutrients to the tumor and allows it to grow and provides a route for metastasis. It is believed some therapies directed at inhibiting stroma formation will inhibit the growth of epithelial tumors from a wide variety of histological types. (George, D. Semin Oncol, 2001. 28 (5 Suppl 17), 27-33; Shaheen, R. M., et al., Cancer Res, 2001. 61 (4), 1464-8; Shaheen, R. M., et al. Cancer Res, 1999. 59 (21), 5412-6). However, because of the complex nature and the multiple growth factors involved in angiogenesis process and tumor progression, an agent targeting a single pathway may have limited efficacy. It is desirable to provide treatment against a number of key signaling pathways utilized by tumors to induce angiogenesis in the host stroma. These include PDGF, a potent stimulator of stroma formation (Ostman, A. and C. H. Heldin, Adv Cancer Res, 2001, 80, 1-38), FGF, a chemo-attractant and mitogen for fibroblasts and endothelial cells, and VEGF, a potent regulator of vascularization.
A major regulator of angiogenesis and vasculogenesis in both embryonic development and some angiogenic-dependent diseases is vascular endothelial growth factor (VEGF; also called vascular permeability factor, VPF). VEGF represents a family of isoforms of mitogens existing in homodimeric forms due to alternative RNA splicing. The VEGF isoforms are reported to be highly specific for vascular endothelial cells (for reviews, see: Farrara et al. Endocr. Rev. 1992, 13, 18; Neufield et al. FASEB J. 1999, 13, 9).
VEGF expression is reported to be induced by hypoxia (Shweiki et al. Nature 1992, 359, 843), as well as by a variety of cytokines and growth factors, such as interleukin-1, interleukin-6, epidermal growth factor and transforming growth factor. To date, VEGF and the VEGF family members have been reported to bind to one or more of three transmembrane receptor tyrosine kinases (Mustonen et al. J. Cell Biol., 1995, 129, 895), VEGF receptor-1 (also known as flt-1 (fms-like tyrosine kinase-1)), VEGFR-2 (also known as kinase insert domain containing receptor (KDR); the murine analogue of KDR is known as fetal liver kinase-1 (flk-1)), and VEGFR-3 (also known as flt-4). KDR and flt-1 have been shown to have different signal transduction properties (Waltenberger et al. J. Biol. Chem. 1994, 269, 26988); Park et al. Oncogene 1995, 10, 135). Thus, KDR undergoes strong ligand-dependant tyrosine phosphorylation in intact cells, whereas flt-1 displays a weak response. Thus, binding to KDR is believed to be a critical requirement for induction of the full spectrum of VEGF-mediated biological responses.
In vivo, VEGF plays a central role in vasculogenesis, and induces angiogenesis and permeabilization of blood vessels. Deregulated VEGF expression contributes to the development of a number of diseases that are characterized by abnormal angiogenesis and/or hyperpermeability processes. It is believed regulation of the VEGF-mediated signal transduction cascade by some agents can provide a useful mode for control of abnormal angiogenesis and/or hyperpermeability processes.
The vascular endothelial growth factors (VEGF, VEGF-C, VEGF-D) and their receptors (VEGFR2, VEGFR3) are not only key regulators of tumor angiogenesis, but also lymphangiogenesis. VEGF, VEGF-C and VEGF-D are expressed in most tumors, primarily during periods of tumor growth and, often at substantially increased levels. VEGF expression is stimulated by hypoxia, cytokines, oncogenes such as ras, or by inactivation of tumor suppressor genes (McMahon, G. Oncologist 2000, 5 (Suppl. 1), 3-10; McDonald, N. Q.; Hendrickson, W. A. Cell 1993, 73, 421-424).
The biological activities of the VEGFs are mediated through binding to their receptors. VEGFR3 (also called Flt-4) is predominantly expressed on lymphatic endothelium in normal adult tissues. VEGFR3 function is needed for new lymphatic vessel formation, but not for maintenance of the pre-existing lymphatics. VEGFR3 is also upregulated on blood vessel endothelium in tumors. Recently VEGF-C and VEGF-D, ligands for VEGFR3, have been identified as regulators of lymphangiogenesis in mammals. Lymphangiogenesis induced by tumor-associated lymphangiogenic factors could promote the growth of new vessels into the tumor, providing tumor cells access to systemic circulation. Cells that invade the lymphatics could find their way into the bloodstream via the thoracic duct. Tumor expression studies have allowed a direct comparison of VEGF-C, VEGF-D and VEGFR3 expression with clinicopathological factors that relate directly to the ability of primary tumors to spread (e.g., lymph node involvement, lymphatic invasion, secondary metastases, and disease-free survival). In many instances, these studies demonstrate a statistical correlation between the expression of lymphangiogenic factors and the ability of a primary solid tumor to metastasize (Skobe, M. et al. Nature Med. 2001, 7 (2), 192-198; Stacker, S. A. et al. Nature Med. 2001, 7 (2), 186-191; Makinen, T. et al. Nature Med. 2001, 7 (2), 199-205; Mandriota, S. J. et al. EMBO J. 2001, 20 (4), 672-82; Karpanen, T. et al. Cancer Res. 2001, 61 (5), 1786-90; Kubo, H. et al. Blood 2000, 96 (2), 546-53).
Hypoxia appears to be an important stimulus for VEGF production in malignant cells. Activation of p38 MAP kinase is required for VEGF induction by tumor cells in response to hypoxia (Blaschke, F. et al. Biochem. Biophys. Res. Commun. 2002, 296, 890-896; Shemirani, B. et al. Oral Oncology 2002, 38, 251-257). In addition to its involvement in angiogenesis through regulation of VEGF secretion, p38 MAP kinase promotes malignant cell invasion, and migration of different tumor types through regulation of collagenase activity and urokinase plasminogen activator expression (Laferriere, J. et al. J. Biol. Chem. 2001, 276, 33762-33772; Westermarck, J. et al. Cancer Res. 2000, 60, 7156-7162; Huang, S. et al. J. Biol. Chem. 2000, 275, 12266-12272; Simon, C. et al. Exp. Cell Res. 2001, 271, 344-355). Moreover, VEGF activates the extracellular signal-regulated protein kinase (ERK) in human umbilical vein endothelial cells (HUVEC) (Yu, Y.; Sato, D. J. Cell Physiol 1999, 178, 235-246).
The VEGF-VEGFR2 signaling pathway has been extensively characterized as an important regulator of angiogenesis. Mice lacking VEGFR2 (Flk-1) are almost completely lacking in vasculature and have very few endothelial cells (Shalaby et al., Nature, 1995, 376, 62-66). VEGF is a potent mitogen for endothelial cells, promotes angiogenic sprouting, and increases vascular permeability (reviewed in Yancopoulos et al. Nature 2000, 407, 242). Administration of soluble VEGFR2 inhibits the growth of wide variety of tumors (Shirakawa et al. Int J Cancer, 2002, 99, 244, Bruns et al. Cancer, 2000, 89, 495, Millauer et al., Nature 1994, 367, 576). Similarly, neutralizing antibodies to VEGF (Kim et al., Nature, 1993, 262, 841) or VEGFR2 (Prewett et al., Cancer Res 1999, 59, 5209), as well as VEGF antisense (Saleh et al. Cancer Res 1996, 56, 393) suppress tumor growth in vivo. Furthermore, small molecule inhibitors of VEGFR2 have been shown to inhibit tumor growth in preclinical xenograft models (reviewed in Shepherd and Sridhar, Lung Cancer, 2003, 41, S63) and are being tested in clinical trials. A monoclonal antibody to VEGF (Avastin™) was recently approved for use in combination with other anticancer drugs for treatment of advanced colon cancer.
The Ang-Tie2 signal transduction pathway also plays a key role in vascular formation, particularly with respect to remodeling and stabilization of vessels. The major ligands for Tie2, Angiopoietin-1 and Angiopoietin-2 (Ang1 and Ang2), have distinct activities. While Ang1 is a Tie2 agonist, promoting vessel maturation and stability, Ang2 is partial Tie2 agonist/antagonist having varied activities that are dependent on the tissue and growth factor context (Yancopoulos et al. Nature, 2000, 407, 242). When the local concentration of VEGF is low, Ang2 promotes vessel regression, whereas in areas where VEGF concentrations are high, Ang2 induces vessel destabilization and branching (Holash et al. Ocogene, 1999, 18, 5356). This latter situation is likely the case during active tumor angiogenesis. Ang1 has been shown to regulate endothelial cell survival (Kwak et al. FEBS, 1999, 448, 249, Bussolati et al. FEBS, 2003, 9, 1159) and migration (Witzenbichler et al. J. Biol Chem, 1998, 373, 18514). The role of Ang-Tie2 signaling in tumor angiogenesis is supported by numerous xenograft tumor studies involving the administration of soluble Tie2. Significant inhibition of tumor growth by soluble Tie2 was observed in the WIBC-9 and MC-5 human breast tumors (Shirakawa et al. Int J Cancer, 2002, 99, 344), C26 colon and TS/A breast tumors, R3230AC breast tumor (Lin et al. J Clin Invest, 1997, 100, 2072), A375v melanoma (Siemeister et al. Cancer Res, 1999, 59, 3185), as well as 4T1 murine mammary and B16F10.9 murine melanoma tumors.
The central role of the FGF-FGFR1 signal transduction pathway in angiogenesis is well established. The FGF family includes 22 members expressed from different genes and having distinct activities (Ornitz and Itoh, Genome Biology, 2001, 2, reviews 3005). During mammalian development, FGF1 and FGF2 regulate branching morphogenesis in tissues undergoing vascularization. Administration of FGFs can promote neovascularization in ischemic tissues (Yanagisawa-Miwa et al., Science, 1992, 257, 1401, Tabata et al Cardiovasc Res, 1997, 35, 470). FGFR1 binds FGF1 and FGF2 with similar affinity (Dionne et al., EMBO J, 1990, 9, 2685). The FGF-FGFR1 pathway has also been associated with angiogenesis in a variety of tumor types. FGF2 is a key regulator of angiogenesis in prostate cancer (Doll et al. Prostate, 2001, 49, 293) and melanomas (Straume and Akslen Am J Pathol, 2002, 160, 1009). In addition, antisense targeting of FGFR1 (Wang and Becker Nat Med, 1997, 3, 887) or anti-FGF2 antibodies (Rofstad and Halsor Cancer Res, 2000, 60, 4932) inhibit tumor growth and angiogenesis in human melanomas. Similarly, expression of soluble FGFR decreases the growth of spontaneous pancreatic tumors in mice (Compagni et al. Cancer Res, 2000, 60, 7163), as well as xenografted pancreatic tumors (Wagner et al. Gastroenterology, 1998, 114, 798). Overexpression and amplification of the FGFR1 gene in human breast tumors (Jacquemier et al. Int J Cancer, 1994, 59, 373) and bladder cancers (Simon et al. Cancer Res, 2001, 61, 4514), has been reported whereas translocation of FGFR1 resulting in an activated chimeric kinase has been identified in myeloproliferative disorders with lymphoma (Gausch et al. Mol Cell Biol 2001, 21, 8129) and Chronic Myelogenous Leukemias (CML, Demiroglu et al., Blood, 2001, 98, 3778).
The activation of FGFR1 by FGF induces both the MAPK/ERK and the PI3K/Akt pathways. In contrast to Ang1, which is not a mitogen, FGF stimulates cell proliferation via the MAPK/ERK pathway (Bikfalvi et al., Endocr Rev, 1997, 18, 26). Activation of FGFR1 leads to the recruitment of adaptor proteins FRS2 and GRB2, which recruit SOS to the plasma membrane leading to the activation of RAS (Kouhara et al., Cell, 1997, 89, 693). Activated RAS, which subsequently activates RAF, MEK, then ERK, leads to cell proliferation. The activation of p38 MAPK has also been reported to be involved in FGF-induced cell proliferation (Maher, J Biol Chem, 1999, 274, 17491). The recruitment of GRB2 to activated FGFR1 also recruits Gab1, which induces the PBK/Akt pathway (Ong et al., Mol Cell Biol, 2000, 20, 979), and promotes cell survival. This effect of Akt on cell survival is mediated, in part through mTOR and p70S6K (Gausch et al., Mol Cell, Biol, 2001, 21, 8129). The effects of FGF on cell migration have been shown to be mediated, in part, by ERK activation and c-Fes (reviewed in Javerzat et al., Trends in Molecular Medicine, 2002, 8, 483).
PDGF is another key regulator of stromal formation which is secreted by many tumors in a paracrine fashion and is believed to promote the growth of fibroblasts, smooth muscle and endothelial cells, promoting stroma formation and angiogenesis. PDGF was originally identified as the v-sis oncogene product of the simian sarcoma virus (Heldin, C. H., et al., J Cell Sci Suppl, 1985, 3, 65-76). The growth factor is made up of two peptide chains, referred to as A or B chains which share 60% homology in their primary amino acid sequence. The chains are disulfide cross linked to form the 30 kDa mature protein composed of either AA, BB or AB homo- or heterodimers. PDGF is found at high levels in platelets, and is expressed by endothelial cells and vascular smooth muscle cells. In addition, the production of PDGF is up regulated under low oxygen conditions such as those found in poorly vascularized tumor tissue (Kourembanas, S., et al., Kidney Int, 1997, 51 (2), 438-43). PDGF binds with high affinity to the PDGF receptor, a 1106 amino acid 124 kDa transmembrane tyrosine kinase receptor (Heldin, C. H., A. Ostman, and L. Ronnstrand, Biochim Biophys Acta, 1998. 1378 (1), 79-113). PDGFR is found as homo- or heterodimer chains which have 30% homology overall in their amino acid sequence and 64% homology between their kinase domains (Heldin, C. H., et al. Embo J, 1988, 7 (5), 1387-93). PDGFR is a member of a family of tyrosine kinase receptors with split kinase domains that includes VEGFR2 (KDR), VEGFR3 (Flt4), c-Kit, and FLT3. The PDGF receptor is expressed primarily on fibroblast, smooth muscle cells, and pericytes and to a lesser extent on neurons, kidney mesangial, Leydig, and Schwann cells of the central nervous system. Upon binding to the receptor, PDGF induces receptor dimerization and undergoes auto- and trans-phosphorylation of tyrosine residues which increase the receptors' kinase activity and promotes the recruitment of downstream effectors through the activation of SH2 protein binding domains. A number of signaling molecules form complexes with activated PDGFR including PI-3-kinase, phospholipase C-gamma, src and GAP (GTPase activating protein for p21-ras) (Soskic, V., et al. Biochemistry, 1999, 38 (6), 1757-64). Through the activation of PI-3-kinase, PDGF activates the Rho signaling pathway inducing cell motility and migration, and through the activation of GAP, induces mitogenesis through the activation of p21-ras and the MAPK signaling pathway.
In adults, it is believed the major function of PDGF is to facilitate and increase the rate of wound healing and to maintain blood vessel homeostasis (Baker, E. A. and D. J. Leaper, Wound Repair Regen, 2000. 8 (5), 392-8; Yu, J., A. Moon, and H. R. Kim, Biochem Biophys Res Commun, 2001. 282 (3), 697-700). PDGF is found at high concentrations in platelets and is a potent chemoattractant for fibroblast, smooth muscle cells, neutrophils and macrophages. In addition to its role in wound healing PDGF is known to help maintain vascular homeostasis. During the development of new blood vessels, PDGF recruits pericytes and smooth muscle cells that are needed for the structural integrity of the vessels. PDGF is thought to play a similar role during tumor neovascularization. As part of its role in angiogenesis PDGF controls interstitial fluid pressure, regulating the permeability of vessels through its regulation of the interaction between connective tissue cells and the extracellular matrix. Inhibiting PDGFR activity can lower interstitial pressure and facilitate the influx of cytotoxics into tumors improving the anti-tumor efficacy of these agents (Pietras, K., et al. Cancer Res, 2002. 62 (19), 5476-84; Pietras, K., et al. Cancer Res, 2001. 61 (7), 2929-34).
PDGF can promote tumor growth through either the paracrine or autocrine stimulation of PDGFR receptors on stromal cells or tumor cells directly, or through the amplification of the receptor or activation of the receptor by recombination. Over expressed PDGF can transform human melanoma cells and keratinocytes (Forsberg, K., et al. Proc Natl Acad Sci USA., 1993. 90 (2), 393-7; Skobe, M. and N. E. Fusenig, Proc Natl Acad Sci USA, 1998. 95 (3), 1050-5), two cell types that do not express PDGF receptors, presumably by the direct effect of PDGF on stroma formation and induction of angiogenesis. This paracrine stimulation of tumor stroma is also observed in carcinomas of the colon, lung, breast, and prostate (Bhardwaj, B., et al. Clin Cancer Res, 1996, 2 (4), 773-82; Nakanishi, K., et al. Mod Pathol, 1997, 10 (4), 341-7; Sundberg, C, et al. Am J Pathol, 1997, 151 (2), 479-92; Lindmark, G., et al. Lab Invest, 1993, 69 (6), 682-9; Vignaud, J. M., et al, Cancer Res, 1994, 54 (20), 5455-63) where the tumors express PDGF, but not the receptor. The autocrine stimulation of tumor cell growth, where a large faction of tumors analyzed express both the ligand PDGF and the receptor, has been reported in glioblastomas (Fleming, T. P., et al. Cancer Res, 1992, 52 (16), 4550-3), soft tissue sarcomas (Wang, J., M. D. Coltrera, and A. M. Gown, Cancer Res, 1994, 54 (2), 560-4) and cancers of the ovary (Henriksen, R., et al. Cancer Res, 1993, 53 (19), 4550-4), prostate (Fudge, K., C. Y. Wang, and M. E. Stearns, Mod Pathol, 1994, 7 (5), 549-54), pancreas (Funa, K., et al. Cancer Res, 1990, 50 (3), 748-53) and lung (Antoniades, H. N., et al., Proc Natl Acad Sci USA, 1992, 89 (9), 3942-6). Ligand independent activation of the receptor is found to a lesser extent but has been reported in chronic myelomonocytic leukemia (CMML) where the a chromosomal translocation event forms a fusion protein between the Ets-like transcription factor TEL and the PDGF receptor. In addition, activating mutations in PDGFR have been found in gastrointestinal stromal tumors in which c-Kit activation is not involved (Heinrich, M. C., et al., Science, 2003, 9, 9).
Certain PDGFR inhibitors will interfere with tumor stromal development and are believed to inhibit tumor growth and metastasis.
Several new drugs that are directed at various molecular targets have been approved over the past several years for the treatment of cancer. Imatinib is an inhibitor of the Abl tyrosine kinase and was the first small molecule tyrosine kinase inhibitor to be approved for the treatment of chronic myeloid leukemia (CML). Based on additional activity of imatinib against the receptor tyrosine kinase activated in gastrointestinal stromal tumors (GIST), c-KIT, it was subsequently approved for the treatment of advanced GIST. Erlotinib, a small molecule inhibitor of EGFR, was approved in late 2004 for the treatment of non-small cell lung carcinoma (NSCLC). Sorafenib, an inhibitor of multiple kinases including c-Raf and VEGFR2 was approved for the treatment of advanced renal cell carcinoma (RCC) in December, 2005. Recently in January of 2006, Sunitinib, a multi-kinase inhibitor was approved for the treatment of refractory- or resistant-GIST and advanced RCC. These small molecule inhibitors demonstrate that targeted approaches are successful for the treatment of different types of cancers.
Despite advancements in the art, there remains a need for cancer treatments and anti-cancer compounds.
Compounds and compositions described herein, including salts, metabolites, solvates, solvates of salts, hydrates, prodrugs such as esters, polymorphs, and stereoisomeric forms thereof, exhibit anti-proliferative and anti-angiogenic activity, and are thus useful to prevent or treat the disorders associated with hyper-proliferation and angiogenesis.